Alpha interferon (IFN-α) induces the transfer of resistance to hepatitis B virus (HBV) from liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes. However, little is known about the entry machinery and pathway involved in the transmission of IFN-α-induced antiviral activity. In this study, we found that macrophage exosomes uniquely depend on T cell immunoglobulin and mucin receptor 1 (TIM-1), a hepatitis A virus (HAV) receptor, to enter hepatocytes for delivering IFN-α-induced anti-HBV activity. Moreover, two primary endocytic routes for virus infection, clathrin-mediated endocytosis (CME) and macropinocytosis, collaborate to permit exosome entry and anti-HBV activity transfer. Subsequently, lysobisphosphatidic acid (LBPA), an anionic lipid closely related to endosome penetration of virus, facilitates membrane fusion of exosomes in late endosomes/multivesicular bodies (LEs/MVBs) and the accompanying exosomal cargo uncoating. Together, our findings provide comprehensive insights into the transmission route of macrophage exosomes to efficiently deliver IFN-α-induced antiviral substances and highlight the similarities between the entry mechanisms of exosomes and virus.IMPORTANCE Our previous study showed that LNPC-derived exosomes could transmit IFN-α-induced antiviral activity to HBV replicating hepatocytes, but the concrete transmission mechanisms, which include exosome entry and exosomal cargo release, remain unclear. In this study, we found that virus entry machinery and pathway were also applied to exosome-mediated cell-to-cell antiviral activity transfer. Macrophage-derived exosomes distinctively exploit hepatitis A virus receptor for access to hepatocytes. Later, CME and macropinocytosis are utilized by exosomes, followed by exosome-endosome fusion for efficient transfer of IFN-α-induced anti-HBV activity. We believe that understanding the cellular entry pathway of exosomes will be beneficial to designing exosomes as efficient vehicles for antiviral therapy.
Background
To compare the efficacy and safety of gonioscopy-assisted transluminal trabeculotomy (GATT) and Kahook Dual Blade (KDB) excisional goniotomy in patients with uncontrolled juvenile open-angle glaucoma (JOAG).
Methods
Thirty-three patients (46 eyes) were included in this single-center, retrospective, comparative study and treated with GATT (36 eyes) or KDB goniotomy (13 eyes). Intraocular pressure (IOP), number of glaucoma medications, adverse events, and additional anti-glaucoma procedures were collected during pre- and postoperative visits. Surgical success was defined as 6 mmHg ≤ IOP ≤ 18 mmHg and ≥ 20% IOP reduction from baseline with (partial success) or without (complete success) IOP-lowering medications.
Results
The mean ± SD preoperative IOP was 30.48 ± 12.9 mmHg and 26.08 ± 13.1 mmHg (P = 0.164) on 3.71 ± 0.46 and 3.08 ± 0.86 (P = 0.023) glaucoma medications in GATT and KDB group, respectively. At 3 months, the mean ± SD IOP was 15.48 ± 5.93 mmHg and 20.0 ± 10.8 mmHg after GATT and KDB, respectively (P = 0.072). The percentage of IOP lowering from baseline was 44.4 in the GATT group and 14.1 in the KDB group (P = 0.011). The mean reduction in medications was 2.6 ± 1.7 and 0.8 ± 1.2 three months after GATT and KDB, respectively (P < 0.001). Cumulative proportion of partial and complete success were 65.6 and 44.7% in the GATT group, 30.8 and 15.4% in the KDB group at 6 months. Additional procedures were required in 13.9% of cases after GATT and in 61.5% after KDB (P = 0.001). Patients in the GATT group with prior anti-glaucoma procedures and postoperative IOP spikes were more likely to fail, while those with complete trabeculotomy had a better prognosis.
Conclusions
Reduction of IOP and medications were greater after GATT in uncontrolled JOAG eyes. Whereas, more additional IOP-lowering procedures were required after KDB goniotomy.
Trial registration
This study was registered under the Chinese Clinical Trial Registry (ChiCTR2000034172, 27/06/2020).
Polydopamine–polyethylenimine nanoparticles (PDA/PEI NPs) have been successfully applied as miRNA carriers, and PDA/PEI NPs/miR-21-5p plays a role in increasing the aqueous humor drainage and lowering the intraocular pressure.
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